Methylphenidate

To study the efficacy of methylphenidate for relief of depressive symptoms in patients with advanced cancer.

Patients who indicated some depressive symptoms from screening were randomized to receive methylphenidate ranging from 10-45 mg daily for 28 days. Doses were adjusted according to individual patient need and toxicity evaluation according to a protocol established for the study. Patient visits and evaluation occurred at days 0, 2, 7, 14, 21, and 28 either in the clinic or the patients’ homes. Patients who completed at least eight days of involvement were included in intent-to-treat analysis using the last measure carried forward.

• N = 69  
• MEDIAN AGE = 72 years (range = 40-87)
• MALES: 58%,FEMALES: 42%
• KEY DISEASE CHARACTERISTICS: Multiple tumor types. Average Karnofsky score range = 50-70
• OTHER KEY SAMPLE CHARACTERISTICS: About 75% had clinically significant HADS depression scores at baseline, and slightly less than 50% had clinically relevant anxiety scores. All had a life expectance of at least one month.

• SITE: Multi-site  
• SETTING TYPE: Multiple settings  
• LOCATION: Spain

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care 

• Double blind, randomized, placebo controlled

• Hospital Anxiety and Depression Scale (HADS)
• Edmonton Symptom Assessment Scale (ESAS)

Methylphenidate administration was not significantly better than placebo for symptoms of depression or anxiety and was associated with more adverse events. The evidence regarding efficacy of methylphenidate is inconclusive.

• Small sample (less than 100)
• Other limitations/explanation: Study was underpowered

This study sample was not large enough to enable firm conclusions from this individual study; however, findings did not show a benefit of methylphenidate and showed more adverse events that may be associated with methylphenidate. These results are not supportive for use of methylphenidate in the management of anxiety and depressive symptoms in patients with advanced cancer.

To compare the effectiveness of immediate-release and sustained-release methylphenidate versus modafinil in improving cognitive function in patients with primary brain tumors.

Patients were randomized to receive one of the following three interventions for a total of four weeks:  immediate-release methylphenidate, 10 mg twice daily; sustained-release methylphenidate, 18 mg daily; or modafinil, 200 mg daily. Neurocognitive tests were performed prior to the intervention and were repeated approximately 30 days later, after completion of the intervention.

• Twenty-four patients with primary brain tumors were included.
• Mean age was 44.98 years.
• The sample was 54% male and 46% female.
• Most (62.5%) of patients’ tumors were in the left hemisphere.
• Prior treatment history included radiation therapy (83%) and chemotherapy (87.5%). Of all the participants, 62.5% received chemotherapy during the study.

• Single site
• Outpatient
• MD Anderson Cancer Center, Houston, Texas

Patients were undergoing multiple phases of care.

The study was a randomized, clinical trial.

Objective Cognitive Function Instruments

• Wechsler Adult Intelligence Scale, third edition (WAIS-III) Digit Span and Digit Symbol subtests
• Trail Making Test (TMT) Parts A and B
• Hopkins Verbal Learning Test (HVLT) Immediate Recall, Delayed Recall, and Delayed Recognition Trials
• Multilingual Aphasia Examination Controlled Oral Word Association (MAE COWA) category
• Lafayette Instrument Grooved Pegboard Test

Subjective Anxiety Instruments

• State-Trait Anxiety Inventory (STAI) to measure state and trait anxiety  
• Profile of Mood States (POMS) to measure tension and anxiety

Subjective Depression Instruments

• Beck Depression Inventory (BDI)
• Profile of Mood States (POMS) Questionnaire, Depression-Dejection Scale

Subjective Fatigue Instruments

• Brief Fatigue Inventory (BFI)
• POMS questionnaire, Fatigue-Inertia Scale

Subjective Sleep-Wake Disturbance Instrument

• Brief Sleep Disturbance Scale (BSDS)

• Over time, no differences were found in cognitive function in regard to attention or motor function.
• Over time, mixed results were found in regard to the speed of processing:
  • The WAIS-III Digit Symbol subtest showed significant improvement (p = 0.02), but TMT Part A did not.
  • The HVLT Delayed Recognition Trial showed a signficiant decline (p = 0.03) in memory, but the other memory-related trials did not.
• In regard to the use of either stimulant and executive function over time, the TMT Part B score improved significantly (p = 0.02); however, the MAE COWA score declined significantly (p = 0.02).
• In regard to differences between the methylphenidate and modafinil treatment groups over time, researchers found the following:
  • A significant difference (p = 0.05) in attention. Attention-related scores of patients taking methylphenidate were stable on the WAIS-III Digit Span subtest; the scores of patients taking modafinil worsened over time.
  • A difference in the speed of processing as measured by TMT Part A. Patients using modafinil improved in comparison to patients taking methylphenidate, whose scores either remained stable or declined slightly (p = 0.05).
• In regard to subjective measures of other symptoms, researchers noted, with use of either stimulant over time:
  • Significant improvement (p < 0.01) of depression, as measured by the BDI and POMS Depression-Dejection Scale.
  • Significant improvement (p = 0.04) of fatigue, as measured by the BFI.
  • Significant improvement of fatigue (p < 0.01), as measured by the POMS Fatigue-Inertia Scale.
  • Significant improvement (p = 0.03) of anxiety, as measured by the state subtest of the STAI.
• No differences were found over time in regard to sleep-wake disturbances.
• No differences were found between treatment groups in subjective symptom measures over time.

Although this study revealed some improvements in specific cognitive domains over time (e.g., executive function, speed of processing), it is unclear whether these improvements were due to the use of a stimulant; a specific medication (modafinil versus methylphenidate); or other variables, such as practice effects related to the absence of alternative neuropsychological tests. Making definitive interpretations based on this small study is difficult because the findings were confounded by the use of two stimulants (one with two different dosage schedules) and the lack of a control group (patients who were not receiving stimulants).

• The study had a small sample size, with less than 30 participants.
• The study had risks of bias due to no control group and no blinding.
• Participant withdrawals were 10% or greater.
• The investigators were unable to achieve the sample size recommended by the power analysis due to poor accrual and a high drop-out rate (29%). Treatment groups differed significantly in regard to age (p = 0.02) and gender (p = 0.03). Age and gender influence neuropsychological test results.

No evidence was provided to support the use of stimulants to improve cognitive function. The study supports the conduct of future research of this topic in studies with larger sample sizes and in randomized, clinical trials with a nonintervention arm.